tbuckley/cabot-search huggingface dataset:
Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study
Authors: Oluwadolapo D. Lawal, Herbert D. Aronow, Fisayomi Shobayo, Anne L. Hume, Tracey H. Taveira, Kelly L. Matson, Yichi Zhang, Xuerong Wen
Journal: Circulation (2023)

The benefit-risk profile of direct oral anticoagulants (DOACs) compared with warfarin, and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease is unclear. We conducted a new-user, retrospective cohort study of patients with AF and chronic liver disease who were enrolled in a large, US-based administrative database between January 1, 2011, and December 31, 2017. We assessed the effectiveness and safety of DOACs (as a class and individually) compared with warfarin, and between DOACs in patients with AF and chronic liver disease. The primary outcomes were hospitalization for ischemic stroke/systemic embolism and hospitalization for major bleeding. Inverse probability treatment weights were used to balance the treatment groups on measured confounders. Overall, 10 209 participants were included, with 4421 (43.2%) on warfarin, 2721 (26.7%) apixaban, 2211 (21.7%) rivaroxaban, and 851 (8.3%) dabigatran. The incidence rates per 100 person-years for ischemic stroke/systemic embolism were 2.2, 1.4, 2.6, and 4.4 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. The incidence rates per 100 person-years for major bleeding were 7.9, 6.5, 9.1, and 15.0 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. After inverse probability treatment weights, the risk of hospitalization for ischemic stroke/systemic embolism was significantly lower between DOACs as a class (hazard ratio [HR], 0.64 [95% CI, 0.46-0.90]) or apixaban (HR, 0.40 [95% CI, 0.19-0.82]) compared with warfarin, but not significantly different between rivaroxaban versus warfarin (HR, 0.76 [95% CI, 0.47-1.21]) or rivaroxaban versus apixaban (HR, 1.73 [95% CI, 0.91-3.29]). Compared with warfarin, the risk of hospitalization for major bleeding was lower with DOACs as a class (HR, 0.69 [95% CI, 0.58-0.82]), apixaban (HR, 0.60 [95% CI, 0.46-0.78]), and rivaroxaban (HR, 0.79 [95% CI, 0.62-1.0]). However, the risk of hospitalization for major bleeding was higher for rivaroxaban versus apixaban (HR, 1.59 [95% CI, 1.18-2.14]). Among patients with AF and chronic liver disease, DOACs as a class were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding versus warfarin. However, the incidence of clinical outcomes among patients with AF and chronic liver disease varied between individual DOACs and warfarin, and in head-to-head DOAC comparisons.
The endogenous repertoire harbors self-reactive CD4+ T cell clones that adopt a follicular helper T cell-like phenotype at steady state
Authors: Victoria Lee, Donald M. Rodriguez, Nicole K. Ganci, Sharon Zeng, Junting Ai, Jaime L. Chao, Matthew T. Walker, Christine H. Miller, David E. J. Klawon, Mary H. Schoenbach, Domenick E. Kennedy, Mark Maienschein-Cline, Nicholas D. Socci, Marcus R. Clark, Peter A. Savage
Journal: Nature Immunology (2023)
Association of Long-term Exposure to Air Pollution With Late-Life Depression in Older Adults in the US
Authors: Xinye Qiu, Liuhua Shi, Laura D. Kubzansky, Yaguang Wei, Edgar Castro, Haomin Li, Marc G. Weisskopf, Joel D. Schwartz
Journal: JAMA Network Open (2023)

Emerging evidence has suggested harmful associations of air pollutants with neurodegenerative diseases among older adults. However, little is known about outcomes regarding late-life mental disorders, such as geriatric depression.To investigate if long-term exposure to air pollution is associated with increased risk of late-life depression diagnosis among older adults in the US.This population-based longitudinal cohort study consisted of US Medicare enrollees older than 64 years. Data were obtained from the US Centers for Medicare and Medicaid Services Chronic Conditions Warehouse. The participants were continuously enrolled in the Fee-for-Service program and both Medicare Part A and Part B. After the 5-year washout period at entry, a total of 8 907 422 unique individuals were covered over the study period of 2005 to 2016, who contributed to 1 526 690 late-onset depression diagnoses. Data analyses were performed between March 2022 and November 2022.The exposures consisted of residential long-term exposure to fine particulate matter (PM2.5), measured in micrograms per cubic meter; nitrogen dioxide (NO2), measured in parts per billion; and ozone (O3), measured in parts per billion.Late-life depression diagnoses were identified via information from all available Medicare claims (ie, hospital inpatient, skilled nursing facility, home health agency, hospital outpatient, and physician visits). Date of the first occurrence was obtained. Hazard ratios and percentage change in risk were estimated via stratified Cox proportional hazards models accounting for climate coexposures, neighborhood greenness, socioeconomic conditions, health care access, and urbanicity level.A total of 8 907 422 Medicare enrollees were included in this study with 56.8% being female individuals and 90.2% being White individuals. The mean (SD) age at entry (after washout period) was 73.7 (4.8) years. Each 5-unit increase in long-term mean exposure to PM2.5, NO2, and O3 was associated with an adjusted percentage increase in depression risk of 0.91% (95% CI, 0.02%-1.81%), 0.61% (95% CI, 0.31%- 0.92%), and 2.13% (95% CI, 1.63%-2.64%), respectively, based on a tripollutant model. Effect size heterogeneity was found among subpopulations by comorbidity condition and neighborhood contextual backgrounds.In this cohort study among US Medicare enrollees, harmful associations were observed between long-term exposure to air pollution and increased risk of late-life depression diagnosis.
A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors
Authors: Ana Ruiz-Saenz, Chloe E. Atreya, Changjun Wang, Bo Pan, Courtney A. Dreyer, Diede Brunen, Anirudh Prahallad, Denise P. Muñoz, Dana J. Ramms, Valeria Burghi, Danislav S. Spassov, Eleanor Fewings, Yeonjoo C. Hwang, Cynthia Cowdrey, Christina Moelders, Cecilia Schwarzer, Denise M. Wolf, Byron Hann, Scott R. VandenBerg, Kevan Shokat, Mark M. Moasser, René Bernards, J. Silvio Gutkind, Laura J. van ‘t Veer, Jean-Philippe Coppé
Journal: Nature Cancer (2023)

Abstract BRAF V600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF–MEK–EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAF V600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E 2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAF V600E CRC.
Association of <scp>Anti‐CCAR1</scp> Autoantibodies With Decreased Cancer Risk Relative to the General Population in Patients With Anti–Transcriptional Intermediary Factor 1γ–Positive Dermatomyositis
Authors: David Fiorentino, Christopher A. Mecoli, Tak Igusa, Jemima Albayda, Julie J. Paik, Eleni Tiniakou, Brittany Adler, Andrew L. Mammen, Ami A. Shah, Antony Rosen, Lisa Christopher‐Stine, Livia Casciola‐Rosen
Journal: Arthritis & Rheumatology (2023)

Objective To describe the disease specificity, clinical phenotype, and risk of cancer in dermatomyositis (DM) patients with autoantibodies against cell division cycle and apoptosis regulator protein 1 (anti‐CCAR1). Methods The frequency of anti‐CCAR1 autoantibodies was measured by enzyme‐linked immunosorbent assay in the serum of DM patients from 2 independent cohorts (Johns Hopkins and Stanford), with patients with several other rheumatic diseases and healthy controls used as comparators. Clinical features and the risk of cancer incidence relative to that in the general population were determined in anti‐CCAR1–positive DM patients. Results Anti‐CCAR1 antibodies were significantly associated with anti–transcriptional intermediary factor 1γ (anti‐TIF1γ) antibodies present in the serum of patients with DM: 80 (32%) of 252 anti‐TIF1γ–positive DM patients versus 14 (8%) of 186 anti‐TIF1γ–negative DM patients were positive for anti‐CCAR1 antibodies ( P &lt; 0.001). Anti‐CCAR1 antibodies were not detected in any of the 32 serum samples from healthy controls, and were present at very low frequencies in the sera of patients with other rheumatic diseases: 1 (2.3%) of 44 patients with anti–hydroxymethylglutaryl‐coenzyme A reductase–positive necrotizing myopathy, 1 (2.3%) of 44 patients with inclusion body myositis, and 3 (6.5%) of 46 patients with systemic lupus erythematosus were positive for anti‐CCAR1 antibodies. Upon examining data on occurrence of cancer from the onset of DM onward, the observed number of cancers diagnosed in anti–TIF‐1γ–positive DM patients was significantly greater than expected in both cohorts, with a standardized incidence ratio (SIR) of 3.49 (95% confidence interval [95% CI] 2.39–4.92) in the Johns Hopkins cohort and a SIR of 4.54 (95% CI 3.04–6.52) in the Stanford cohort (each P &lt; 0.001). DM patients who were both anti‐TIF1γ positive and anti‐CCAR1 positive had lower SIRs for cancer, with a SIR of 1.78 (95% CI 0.77–3.51) ( P = 0.172) in the Johns Hopkins cohort and a SIR of 1.61 (95% CI 0.44–4.13) ( P = 0.48) in the Stanford cohort. Conclusion Anti‐CCAR1 autoantibodies are specific for anti‐TIF1γ–positive DM. Their presence in anti‐TIF1γ–positive patients attenuates the risk of cancer to a level comparable to that seen in the general population. image
Dysregulation of developmental and cell type-specific expression of glycoconjugates on hematopoietic cells: a new characteristic of myelodysplastic neoplasms (MDS)
Authors: Margot F. van Spronsen, Sophie Horrevorts, Claudia Cali, Theresia M. Westers, Sofie Van Gassen, Yvan Saeys, Sandra J. van Vliet, Yvette van Kooyk, Arjan A. van de Loosdrecht
Journal: Leukemia (2023)
An EU task force to assess the burden of rare diseases
Authors: Pavel Kolkhir, Diana Alecsandra Grad, Periklis Charalampous, Claudia Cruz Oliveira, Enkeleint A. Mechili, Brigid Unim, David A. Pearce, Marcus Maurer, Brecht Devleesschauwer, Juanita Haagsma
Journal: Nature Medicine (2023)
A One‐Stone‐Two‐Birds Strategy for Osteochondral Regeneration Based on a 3D Printable Biomimetic Scaffold with Kartogenin Biochemical Stimuli Gradient
Authors: Wenying Wei, Wenbin Liu, Haifei Kang, Xiangke Zhang, Ran Yu, Jiawei Liu, Kai Huang, Yiqian Zhang, Mingsheng Xie, Yihe Hu, Honglian Dai
Journal: Advanced Healthcare Materials (2023)

Abstract Osteochondral defect (OCD) regeneration remains challenging because of the hierarchy of the native tissue including both the articular cartilage and the subchondral bone. Constructing an osteochondral scaffold with biomimetic composition, structure, and biological functionality is the key to achieve its high‐quality repair. In the present study, an injectable and 3D printable bilayered osteochondral hydrogel based on compositional gradient of methacrylated sodium alginate, gelatin methacryloyl, and β ‐tricalcium phosphate ( β ‐TCP), as well as the biochemical gradient of kartogenin (KGN) in the two well‐integrated zones of chondral layer hydrogel (CLH) and osseous layer hydrogel (OLH) is developed. In vitro and subcutaneous in vivo evaluations reveal that apart from the chondrogenesis of the embedded bone mesenchymal stem cells induced by CLH with a high concentration of KGN, a low concentration of KGN with β ‐TCP in the OLH synergistically achieves superior osteogenic differentiation by endochondral ossification, instead of the intramembranous ossification using OLH with only β ‐TCP. The biomimetic construct leveraging KGN as the only biochemical inducer can facilitate cartilage and subchondral bone restoration in the in vivo osteochondral defect. This one‐stone‐two‐birds strategy opens up a new facile approach for OCD regeneration by exploiting the biological functions of the bioactive drug molecule KGN.
Integrated cardio-behavioral responses to threat define defensive states
Authors: Jérémy Signoret-Genest, Nina Schukraft, Sara L. Reis, Dennis Segebarth, Karl Deisseroth, Philip Tovote
Journal: Nature Neuroscience (2023)

Abstract Fear and anxiety are brain states that evolved to mediate defensive responses to threats. The defense reaction includes multiple interacting behavioral, autonomic and endocrine adjustments, but their integrative nature is poorly understood. In particular, although threat has been associated with various cardiac changes, there is no clear consensus regarding the relevance of these changes for the integrated defense reaction. Here we identify rapid microstates that are associated with specific behaviors and heart rate dynamics, which are affected by long-lasting macrostates and reflect context-dependent threat levels. In addition, we demonstrate that one of the most commonly used defensive behavioral responses—freezing as measured by immobility—is part of an integrated cardio-behavioral microstate mediated by Chx10 + neurons in the periaqueductal gray. Our framework for systematic integration of cardiac and behavioral readouts presents the basis for a better understanding of complex neural defensive states and their associated systemic functions.
Improved Prospects for Thrombectomy in Large Ischemic Stroke
Authors: Pierre Fayad
Journal: New England Journal of Medicine (2023)

Mechanical endovascular thrombectomy, when performed within 24 hours after the onset of symptoms in patients with small-to-moderate acute ischemic strokes that are due to proximal occlusion of a large cerebral vessel, has been shown to result in rates of recanalization of 70 to 80% and to significantly improve functional independence at 90 days.1,2 Thrombectomy represents one of the most effective treatments in medicine: the number needed to treat to prevent disability in one patient with stroke is 2.3. These results, however, do not apply to patients with large strokes, who have been mostly excluded from clinical trials of thrombectomy. Treatment . . .
<i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Ana Vujovic, Laura de Rooij, Ava Keyvani Chahi, He Tian Chen, Brian A. Yee, Sampath K. Loganathan, Lina Liu, Derek C.H. Chan, Amanda Tajik, Emily Tsao, Steven Moreira, Pratik Joshi, Joshua Xu, Nicholas Wong, Zaldy Balde, Soheil Jahangiri, Sasan Zandi, Stefan Aigner, John E. Dick, Mark D. Minden, Daniel Schramek, Gene W. Yeo, Kristin J. Hope
Journal: Blood Cancer Discovery (2023)

Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an in vivo two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9;NrasG12D AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven in vivo leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell-adapted in vivo CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML.LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell-adapted in vivo CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. This article is highlighted in the In This Issue feature, p. 171.
Clinical Outcomes and Hospital Utilization Among Patients Undergoing Bariatric Surgery With Telemedicine Preoperative Care
Authors: Callie Hlavin, Phoebe Ingraham, Tamara Byrd, Nathan Hyre, Lucine Gabriel, Nishant Agrawal, Laura Allen, Tanya Kenkre, Andrew Watson, Murat Kaynar, Bestoun Ahmed, Anita Courcoulas
Journal: JAMA Network Open (2023)

Bariatric surgery is the mainstay of treatment for medically refractory obesity; however, it is underutilized. Telemedicine affords patient cost and time savings and may increase availability and accessibility of bariatric surgery.To determine clinical outcomes and postoperative hospital utilization for patients undergoing bariatric surgery who receive fully remote vs in-person preoperative care.This cohort study comparing postoperative clinical outcomes and hospital utilization after telemedicine or in-person preoperative surgical evaluation included patients treated at a US academic hospital. Participants underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy after telemedicine or in-person preoperative surgical evaluation between July 1, 2020, to December 22, 2021, or January 1, 2018, to December 31, 2019, respectively. Follow-up was 60 days from date of surgery.Telemedicine-based preoperative care.Clinical outcomes, including operating room delay, procedure duration, length of hospital stay (LOS), and major adverse events (MAE), and postoperative hospital resource utilization, including emergency department (ED) visit or hospital readmission within 30 days of the surgical procedure.A total of 1182 patients were included; patients in the telemedicine group were younger (mean [SD] age, 40.8 [12.5] years vs 43.0 [12.2] years; P = .01) and more likely to be female (230 of 257 [89.5%] vs 766 of 925 [82.8%]; P = .01) compared with the control group. The control group had a higher frequency of comorbidity (887 of 925 [95.9%] vs 208 of 257 [80.9%]; P < .001). The telemedicine group was found to be noninferior to the control group with respect to operating room delay (mean [SD] minutes, 7.8 [25.1]; 95% CI, 5.1-10.5 vs 4.2 [11.1]; 95% CI, 1.0-7.4; P = .002), procedure duration (mean [SD] minutes, 134.4 [52.8]; 95% CI, 130.9-137.8 vs 105.3 [41.5]; 95% CI, 100.2-110.4; P < .001), LOS (mean [SD] days, 1.9 [1.1]; 95% CI, 1.8-1.9 vs 2.1 [1.0]; 95% CI, 1.9-2.2; P < .001), MAE within 30 days (3.8%; 95% CI, 3.0%-5.7% vs 1.6%; 95% CI, 0.4%-3.9%; P = .001), MAE between 31 and 60 days (2.2%; 95% CI, 1.3%-3.3% vs 1.6%; 95% CI, 0.4%-3.9%; P < .001), frequency of ER visits (18.8%; 95% CI, 16.3%-21.4% vs 17.9%; 95% CI, 13.2%-22.6%; P = .03), and hospital readmission (10.1%; 95% CI, 8.1%-12.0% vs 6.6%; 95% CI, 3.9%-10.4%; P = .02).In this cohort study, clinical outcomes in the telemedicine group were not inferior to the control group. This observation suggests that telemedicine can be used safely and effectively for bariatric surgical preoperative care.
Novel Somatic <scp><i>UBA1</i></scp> Variant in a Patient With <scp>VEXAS</scp> Syndrome
Authors: Blanka Stiburkova, Katerina Pavelcova, Monika Belickova, Samuel J. Magaziner, Jason C. Collins, Achim Werner, David B. Beck, Veronika Balajkova, Cyril Salek, Martin Vostry, Herman Mann, Jiri Vencovsky
Journal: Arthritis & Rheumatology (2023)

Somatic mutations in UBA1 have recently been causally linked to a severe adult-onset inflammatory condition referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Ubiquitin-activating enzyme E1 (UBA-1) is of fundamental importance to the modulation of ubiquitin homeostasis and to the majority of downstream ubiquitylation-dependent cellular processes. Direct sequencing analysis of exon 3 containing the prevalent variants p.Met41Leu, p.Met41Val, and/or p.Met41Thr is usually used to confirm the disease-associated mutations.
Preexisting evidence and outcome of phase III trials in gastrointestinal oncology: a systematic review
Authors: Giacomo Bregni, Elena Trevisi, Rita Saúde Conde, Michele Vanhooren, Tugba Akin Telli, Irene Assaf, Alain Hendlisz, Massimo Di Maio, Francesco Sclafani
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background A minority of phase III trials in gastrointestinal oncology are positive. We assessed the association between their outcome and the level and characteristics of preexisting evidence. Methods EMBASE, PubMed, and proceedings from international meetings were searched for phase III gastrointestinal cancer trials (gastroesophageal, hepatocellular, biliary tract, pancreatic, small bowel, colorectal, anal, stromal, and neuroendocrine) between January 2000 and June 2020. Trials investigating anticancer drugs for advanced disease, with superiority design and standard treatments as control were eligible. The highest level of preexisting evidence was retrieved from the main study report. Results A total of 193 phase III trials were included, and 69 (35.8%) met their primary endpoint. Positivity rates were as follows: gastroesophageal 37%, colorectal 48%, pancreatic 17.1%, hepatocellular 20%, neuroendocrine 75%, and both biliary tract and GIST 60%. No information about preexisting evidence was found for 44 trials (22.8%). For the remaining 149, preexisting evidence consisted of phase II studies in 123 cases (82.6%) and phase I studies in 26 cases (17.4%). The probability of success was 34.1%, 35.8%, and 35.7%, respectively (P = .934). No parameter from prior studies predicted the outcome of phase III trials except β &amp;lt; .2 (P = .048). A numerically increased success rate was observed for phase III trials preceded by positive phase II studies (41.9% vs 18.5%, P = .2). Conclusions There does not appear to be an association between level of prior evidence and success of phase III gastrointestinal cancer trials. These data, along with the high phase III failure rate, highlight the need to improve the drug development process in this setting.